Abstract
Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf GAP activity. A number of these functions hinge on the remodeling of actin filaments. Accordingly, some of the effects exerted by Arf GAPs involve proteins known to engage in regulation of the actin dynamics and architecture, such as Rho family proteins and nonmuscle myosin 2. Circular dorsal ruffles (CDRs), podosomes, invadopodia, lamellipodia, stress fibers and focal adhesions are among the actin-based structures regulated by Arf GAPs. Arf GAPs are thus important actors in broad functions like adhesion and motility, as well as the specialized functions of bone resorption, neurite outgrowth, and pathogen internalization by immune cells. Arf GAPs, with their multiple protein-protein interactions, membrane-binding domains and sites for post-translational modification, are good candidates for linking the changes in actin to the membrane. The findings discussed depict a family of proteins with a critical role in regulating actin dynamics to enable proper cell function.
Highlights
Coordinated changes in the membrane and actin cytoskeleton underlying several motile cellular structures are critical for normal physiology, including development, wound healing and phagocytosis and contribute to pathological behaviors such as cancer invasion and metastasis [1,2,3]
Five ADP-ribosylation factors (Arfs) GTPase-activating proteins (GAPs) have been shown to associate with podosomes or invadopodia: ASAP1 with podosomes induced by active Src in fibroblasts and invadopodia in cancer cells [29]; ARAP1, GIT1 and GIT2 with podosome belts in osteoclasts [41,63]; and ARAP3 with podosome-like structures in fibroblasts plated on a fluid substrate [50]
ARAP1 isoform2 containing PH3 and 4, Rho GAP, RA and PH5 domain, still targeted to the podosome belt and rescued the defect in sealing zone formation, suggesting that the Rho GAP domain regulates the formation and dynamics of podosome belts [41]. This is different from ARAP1 control of Circular dorsal ruffles (CDRs), wherein Arf GAP instead of Rho GAP activity is required, even though it appeared that the C-terminal half of ARAP1 is the targeting domain in both cases
Summary
Coordinated changes in the membrane and actin cytoskeleton underlying several motile cellular structures are critical for normal physiology, including development, wound healing and phagocytosis and contribute to pathological behaviors such as cancer invasion and metastasis [1,2,3]. Changes in the membrane composition (i.e., phosphoinositides, membrane-associated proteins) or curvature affect the actin dynamics and organization [4,5]. The molecular bases for spatial and temporal control of cellular membrane and actin remodeling in response to a plethora of signals are still being discovered. We discuss the literature supporting the emerging role of the Arf GTPase-activating proteins (Arf GAPs) as part of the interface between the signaling cascade and cellular machinery for remodeling of the membranes and the actin cytoskeleton
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